Role of miR200b-5p miRNA in lymphomagenesis associated with Sjögren's syndrome (SS).

Background: Development of non-Hodgkin's lymphoma (NHL) is the major adverse outcome of primary Sjögren's Syndrome (pSS) affecting both morbidity and mortality. The high frequency of transformation to lymphoid malignancy in pSS among autoimmune rheumatic diseases (6-10% of patients) and the accessibility of the affected organ (minor salivary glands; MSG), render pSS an ideal model for the study of lymphomagenesis associated with autoimmune diseases and inflammation. Although pSS-related lymphoid transformation is generally considered as an antigen-driven, multi-step process owed to the chronic activation of B-cells in MSGs, the underlying mechanisms remain elusive. Our recent results support that miR200b-5p miRNA is significantly down-regulated in the MSGs of pSS patients who have or will develop lymphoma, long before lymphoma clinical onset, indicating that it may be involved in lymphomagenesis.

Aim: To investigate the role of miR200b-5p miRNA in pSS-associated lymphomagenesis.

Methods: At first, the miR200b-5p-expression will be examined by hybridization in MSGs of pSS patients who are at low risk and have not developed NHL during follow-up, high risk and developed NHL in the future (pre-lymphoma) or have NHL, and the expressing cellular types, as well as those with reduced expression during lymphomagenesis, will be identified. Then, the miR200b-5p targeted molecular pathways in those cellular types (epithelial, B-cells and/or other lymphocytes, all non-neoplastic) will be studied in experiments by over-expressing and silencing of miR200b-5p, followed by transcriptome analysis. This approach is expected to find possibly novel pathogenetic mechanisms underlying SS-related lymphomagenesis. The latter is of high significance, not only for the understanding of lymphomagenesis, but also for its reversal and/or treatment.

Anticipated Benefits: This approach is anticipated to a) reveal the differentially regulated molecules and pathways by miR200b-5p, b) enlighten novel pathogenetic pathways underlying lymphomagenesis and c) identify novel therapeutic targets and possibly evidence-based therapeutic interventions.